Shaping the future – From spermatids to spermatozoa | GettingInShape | Proyecto | Ficha informativa | HORIZON | CORDIS

Descripción del proyecto

Dilucidar la especialización de los espermatozoides

Durante mucho tiempo, la búsqueda de una respuesta al misterio de la especialización de los espermatozoides se ha visto obstaculizada por los complejos detalles moleculares que subestiman los investigadores debido a las dificultades de la manipulación genética. Si bien la microscopia electrónica ha favorecido una mejor comprensión de la complejidad de la estructura de los espermatozoides, aún se desconocen sus particularidades moleculares. En el proyecto GettingInShape, financiado por el Consejo Europeo de Investigación, se abordará esta brecha del conocimiento con un método revolucionario. Esta iniciativa, pionera en tomografía crioelectrónica, pretende descifrar los mecanismos que rigen la conformación nuclear, la remodelación de los centríolos, el ensamblaje de las vainas mitocondriales y la activación del aparato motor en las células reproductoras masculinas. Esta investigación no solo tiene implicaciones clínicas para el diagnóstico de la infertilidad, sino que además podría favorecer el desarrollo de un anticonceptivo masculino.

Objetivo

Sperm are highly specialised cells whose structure is optimised for a defined function. Although the distinctive sperm ultrastructure has been known for many years thanks to electron microscopy, an understanding of the molecular details of sperm specialisation is severely lagging. The gap in our molecular understanding relates to the difficulties in genetically manipulating sperm.
Over the past five years, my lab has pioneered the use of cryo-electron tomography to study mature mammalian sperm at the molecular level. We developed workflows based on cryo-focused ion beam milling and sub-tomogram averaging that allowed us to provide the first in-cell structures of mammalian sperm flagella, revealing unique microtubule inner proteins. We further showed that the sperm centrioles and their surrounding matrix form a dynamic basal complex that facilitates a cascade of internal sliding, coupling tail beating with asymmetric head kinking. Although these findings contribute profoundly to the field, the resolution achieved in these studies (~20) precluded protein identification in most cases.
Now I plan to develop a workflow based on single particle analysis, achieving near-atomic resolution, but without purification. I will apply this workflow, together with biochemical assays and cellular cryo-electron tomography, to humans and other species to resolve how germ cells get into shape and acquire motility. Specifically, the mechanisms underlining 1) nuclear shaping 2) centriole remodelling 3) mitochondrial sheath assembly 4) motor apparatus activation.
Understanding how male germ cells get into shape is of clinical relevance, as sperm morphological defects are often observed in infertility. Moreover, the success rate of assisted reproduction technologies can be improved with better diagnosis and we expect that the new proteins we identify will help this process. Conversely, understanding the acquisition of motility could potentially be used to develop a male contraceptive.